1. Field of the Invention
The pharmaceutically active bicyclic heterocyclic amines (XXX) of the present invention are useful as pharmaceuticals to treat a number of diseases and injuries.
2. Description of the Related Art
The bicyclic heterocyclic amines (XXX) of the present invention contain a variety of compounds depending on the definitions of W.sub.1, W.sub.3 and W.sub.5.
When W.sub.1 is --N.dbd., W.sub.3 is --N.dbd. and W.sub.5 is --CR.sub.5 .dbd. the bicyclic heterocyclic amines (XXX) are pyrrolo 2,3-d!)pyrimidines (VII). The pyrrolo 2,3-d!pyrimidine ring system is known. For example, 4-amino-7.beta.-D-ribofuranosyl-7H-pyrrolo 2,3-d!pyrimidine is tubercidin. However, the 2,4-di(tertiary amino)-pyrrolo 2,3-d!pyrimidines of this invention are novel. Other similar compounds have been prepared for study of antiviral and antitumor properties, see Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Roes, Ed., Vol. 4, Pergamon Press, 1984, p. 528.
When W.sub.1 is --N.dbd., W.sub.3 is --CH.dbd. and W.sub.5 is --N.dbd. the bicyclic heterocyclic amines (XXX) are 3H-imidazo 4,5b!pyridines (XXV). This ring system is known, see DE 3 318 671 A1, CA 44, 2041b and Swiss Patent 260,741.
When W.sub.1 is --N.dbd., W.sub.3 is --CH.dbd. and W.sub.5 is --CR.sub.5 .dbd. the bicyclic heterocyclic amines (XXX) are 1H-pyrrolo 2,3-b!pyridines (XI). This ring system is known, see J. Chem. Soc., 101, 1779 (1912).
When W.sub.1 is --CH.dbd., W.sub.3 is --N.dbd. and W.sub.5 is --N.dbd. the bicyclic heterocyclic mines (XXX) are 1H-imidazo 4,5-c!pyridines (XXIX). This ring system is known, see Biochem. Z, 49, 182 (1913).
When W.sub.1 is --CH.dbd., W.sub.3 is --N.dbd. and W.sub.5 is --CR.sub.5 .dbd. the bicyclic heterocyclic amines (XXX) are 1H-pyrrolo 3,2-c!pyridines (XVI). This ring system is known, see J. Chem. Soc., 95, 1526 (1909).
Other substituted amino type compounds which are useful for treating the same diseases and injuries as those of the present invention are disclosed in International Publication No. WO87/01706, published Mar. 26, 1987 based on International Patent Application No. PCT/US86/01797; International Publication No. WO87/07895, published Dec. 30, 1987 based on International Patent Application No. PCT/US87/07895; International Publication No. WO88/08424, published Nov. 3, 1988 based on International Patent Application No. PCT/US88/01212; International Publication No. WO88/07527, published Oct. 6, 1988 based on International Patent Application No. PCT/US88/00817 and U.S. patent application Ser. No. 07/427,143, filed Oct. 25, 1989.
WO92/02500-A discloses 2-phenylindole derivatives useful for treating asthma, allergic disorders, thrombosis and ischaemia.
The J. Heterocyclic. Chem., 24, 425 (1987) EGER! discloses pyrrolopyrimidines where the amino groups on the pyrimidine moiety are free and unsubstituted, whereas the compounds of the present invention are substituted aminopyrrolopyrimidines.
WO91/04254 discloses pyrrolo 2,3-d!)pyrimidines where the groups substituted on the pyrrolo ring are simple. In two of the positions the groups are -H, halogen or alkyl. In the third it is -H, alkyl or aralkyl. The present invention requires that one of R.sub.5 or R.sub.6 is aromatic or heteroaromatic substituted.
J. Heterocyclic Chem., 25, 1633 (1988) discloses pyrimido 4,5-b!indoles with an aromatic ring attached to the 5-member nitrogen containing ring which have antihypertensive activity.
Great Britain Patent 1,268,772 also discloses pyridino-indoles with an aromatic ring attached to the 5-member nitrogen containing ring. These compounds are reported to have antiviral activity in tissue culture experiments.
Great Britain Patent 864,145 discloses imidazolopyrimidines which have analgesic and coronary vasodilation effects.
European Patent 549,886 discloses pyrrolo(2,3-d)pyrimidines useful as anti-neoplastic agents which differ from the compounds of the present invention in that they do not have any substitutent at C.sub.6 and do not include substituted amines for what is R.sub.1 and R.sub.2 of the present invention. Further, the compounds of European Patent 549,886 are prepared by a synthetic route quite different from the method of preparation of the compounds of the present invention.
European Patent 550,574 discloses amino substituted pyrrolopyrimidines useful for immunoregulation of autoimmune and other diseases. The bicyclic heterocyclic amines (XXX) of the present invention include pyrrolopyrimidines however, the pyrrolopyrimidines of the present invention must have the two amino groups on the pyrimidine ring substituted.
International Publication WO92/132074 (European Patent Application 550,574 A1) discloses amino substituted pyrrolopyrimidines useful for immunoregulation of autoimmune and other diseases (rheumatoid arthritis, multiple sclerosis, type I diabetes and viral diseases (HIV). The bicyclic heterocyclic amines (XXX) of the present invention include pyrrolopyrimidines however, the pyrrolopyrimidines of the present invention must have the two substituted amino groups on the pyrimidine ring. Further, the compounds of WO92/132074 do not permit aromatic substitution on the 5-member ring whereas the claimed invention requires aromatic substitution on the 5-membered ring.
International Publication WO 94/13676 (PCT/US9/10715) discloses pyrrolopyrimidines. The examples set forth indicate a strong preference for alkyl (methyl) attached between the pyrimidinyl nitrogen atoms whereas the claimed invention requires an amino group. These compounds were disclosed as being useful for treating depression and anxiety related disorders.
U.S. Pat. No. 5,249,064 discloses pyrrolopyrimidines where the amino substituent between the pyrimidine nitrogen atoms is unsubstituted and the other substituent on the pyrimidine is a amino, hydroxyl or mercapto group which are useful as antitumor agents. The claimed invention requires that the amino group located at the position between the pyrimidine nitrogen atoms be substituted.
U.S. Pat. No. 5,354,754 discloses pyrrolopyrimidines requires at least one of the amino groups on the pyrimidinyl ring to be unsubstituted amino. The present invention requires that both amino groups be substituted.
U.S. Pat. No. 5,354,756 discloses xanthine compounds lowers elevated blood levels of unsaturated, non-arachidonate phosphatic acid and diacylglycerols. The compounds of the present invention expressly prohibit four nitrogen atoms (xanthine ring system) and are useful for a totally different purpose.
International publication WO94/20459 discloses pyrrolopyridines where the substituent attached to the 3-position is piperidinyl or benzofuranyl. These substituents are not permitted in the corresponding position of the claimed invention.
UK Patent Application GB 2,163,150 discloses bicyclic heterocyclic compounds containing at least one nitrogen heteroatom and having a side chain containing an oxygen atom attached via a second oxygen atom to the six member ring. The present invention does not permit the side chain to be attached by an oxygen atom.
JP 6-220,059 discloses 3,2-d!pyrrolopyrimidinyl compounds useful as blood sugar lowering agents whereas the claimed compounds are 2,3-d!pyrrolopyrimidinyl compounds.
JP 6-220,060 discloses bicyclic pyrimidinyl compounds where the substitutents on the pyrimidinyl ring are amino, hydroxy and thio useful as anti-tumor agents whereas the claimed compounds expressly prohibit unsubstituted amino, hydroxy and thio.